Dialysis precursor composition

ABSTRACT

The present invention concerns a dialysis acid precursor composition for use during preparation of a dialysis acid concentrate solution and for mixing with water and a bicarbonate containing concentrate into a ready-for-use dialysis solution. Said dialysis acid precursor composition consists of powder components comprising sodium chloride, at least one dry acid and at least one calcium salt, and optionally potassium salt, magnesium salt, and glucose. According to the invention said at least one calcium salt and said optional glucose, are present as anhydrous components in said dialysis acid precursor composition.

CROSS RELATED APPLICATION

This application is the U.S. national phase of International ApplicationNo. PCT/EP2012/060971 filed 11 Jun. 2012 which designated the U.S. andclaims priority to Swedish Patent Application No. 1150566-6 filed 20Jun. 2011 and U.S. Provisional Patent Application No. 61/499,207 filed21 Jun. 2011, the entire contents these applications are incorporated byreference.

TECHNICAL FIELD

The present invention concerns a dialysis acid precursor composition foruse during preparation of a dialysis acid concentrate solution and forfurther mixing with water and a bicarbonate containing concentrate intoa ready-for-use dialysis solution. The present invention furtherconcerns a method of providing a dialysis acid concentrate solution fordilution with water and a bicarbonate concentrate to produce aready-for-use dialysis solution. Even further, the present inventionconcerns use of said dialysis acid precursor composition for preparationof a dialysis acid concentrate solution, for preparing a dialysissolution, an infusion solution, a replacement solution, a rinsingsolution or a priming solution.

BACKGROUND

When a person's kidney does not function properly uremia is developed.Dialysis is a well established treatment technique for uremia.Essentially, dialysis artificially replaces the functions of the kidney.There are two distinct types of dialysis; hemodialysis and peritonealdialysis.

Hemodialysis involves withdrawing blood from the body and cleaning it inan extracorporeal blood circuit and then returning the cleansed blood tothe body. The extracorporeal blood circuit includes a dialyzer whichcomprises a semipermeable membrane. The semipermeable membrane has ablood side and a dialysate side. Waste substances and excess fluid isremoved from the blood (passing on the blood side of the semipermeablemembrane) through the semipermeable membrane over to the dialysate sideof the semipermeable membrane.

Hemodialysis may be performed in three different treatment modes;hemodialysis, hemofiltration, and hemodiafiltration. Common to all threetreatment modes is that the patient is connected by a blood line to thedialysis machine, which continuously withdraws blood from the patient.The blood is then brought in contact with the blood side of thesemipermeable membrane within the dialyzer in a flowing manner.

In hemodialysis, an aqueous solution called dialysis solution is broughtin contact with the opposite membrane surface, the dialysate side, in aflowing manner. Waste substances (toxins) and solutes areremoved/controlled mainly by diffusion. Excess fluid is removed byapplying a so called transmembrane pressure over the semipermeablemembrane. Solutes and nutrients may diffuse in the opposite directionfrom the dialysis solution, through the semipermeable membrane and intothe blood.

In hemofiltration, no dialysis solution is brought in contact with thedialysate side of the semipermeable membrane. Instead only atransmembrane pressure is applied over the semipermeable membranethereby removing fluid and waste substances from the blood through thesemipermeable membrane wall and into the dialysate side thereof(convective flow). Fluid and waste substances are then passed to drain.To replace some of the removed fluid, a correctly balancedelectrolyte/buffer dialysis solution (also named infusion fluid orreplacement fluid) is infused into the extracorporeal blood circuit.This infusion may be done either pre the dialyzer (pre-infusion mode) orpost the dialyzer (post-infusion mode) or both.

Hemodiafiltration is a combination of hemodialysis and hemofiltration, atreatment mode that combines transport of waste substances and excessfluids through the semipermeable membrane wall by both diffusion andconvection. Thus, here a dialysis solution is brought in contact withthe dialysate side of the semipermeable membrane in a continuouslyflowing manner, and a dialysis solution (also named infusion fluid orreplacement fluid) is used for infusion into the extracorporeal bloodcircuit in pre-infusion mode, post-infusion mode or both.

For many patients, hemodialysis is performed for 3-5 hours, three timesper week. It is usually performed at a dialysis centre, although homedialysis is also possible. When home dialysis is performed the patientis free to perform dialysis more frequently and also in a more gentletreatment with longer duration, i.e. 4-8 hours per treatment and 5-7treatments per week. The dose and treatment duration may be adjusted toeach patient's demands and needs.

In the case of patients suffering from acute renal insufficiency, acontinuous treatment, throughout a major portion of the entire day forup to several weeks, a continuous renal replacement therapy (CRRT), orintermittent renal replacement therapy (IRRT) is the indicated treatmentdepending on the patient's status. Also here the removal of wastesubstances and excess fluid from the patient is effected by any or acombination of the treatment modes hemodialysis, hemofiltration andhemodiafiltration.

In a peritoneal dialysis treatment a hypertonic dialysis solution isinfused into the peritoneal cavity of the patient. In this treatmentsolutes and water is exchanged in the capillary vessels of a patient'speritoneal membrane with said hypertonic dialysis solution. Theprinciple of this method is diffusion of solutes transferred accordingto the concentration gradient and water migration due to the osmoticdifferences over the peritoneal membrane.

The dialysis solutions used in all the above dialysis techniques containmainly electrolytes like sodium, magnesium, calcium, potassium, anacid/base buffer system and optionally glucose or a glucose-likecompound. All the components in dialysis solutions are selected tocontrol the levels of electrolytes and the acid-base equilibrium withinthe blood and to remove waste materials from the blood.

Dialysis solutions are today prepared from different types ofconcentrates. It may be liquid concentrates of different degree ofconcentration, where the acid/electrolyte part is separated from thebuffer part. It may be provided in highly concentrated volumes of 1-8 Lin bags for bedside use, or in more diluted concentrated volumes of 5-20L in canisters, which still are for bedside use. Concentrates may alsobe prepared in central tanks in volumes of 300-1000 L.

When using bicarbonate as a buffer component in the dialysis solution,bicarbonate is often provided as a dry concentrate foron-line-preparation of saturated bicarbonate containing concentrate. Thesaturated bicarbonate containing concentrate is thereafter mixed with anacid/electrolyte concentrate and further diluted with purified water toproduce the on-line prepared dialysis solution.

Dialysis solutions have improved in quality over the years, and theavailability of concentrated precursor compositions for further dilutionand mixing with other components into a ready-for-use dialysis solutionhave decreased the costs and improved the environmental issues.

One way to further limit the costs and improve the environmental issueswould be to provide a dialysis precursor composition in which allcomponents are dry. However, having all components as dry componentsadds new problems.

Firstly, dry acid and bicarbonate powder are not compatible. When asmall amount of humidity is present, bicarbonate will break down tocarbon dioxide.

Secondly, magnesium chloride and calcium chloride mixed with bicarbonatewill provide areas were the solubility product of calcium carbonateand/or magnesium carbonate will be exceeded which would causeprecipitation thereof when water is added during preparation of aconcentrate or a dialysis solution.

Thirdly, even if bicarbonate is excluded to a separate cartridge, stillproblems would be experienced. E.g. caking and lump formation of thedifferent components will render the dissolution thereof more difficultor even impossible when preparing the ready-for-use dialysis solution.

Fourthly, if glucose is present, a discoloration of the precursor, andlater on, the ready-for-use dialysis solution would arise as a result ofglucose degradation products, which should be avoided due to toxicityand limits set by authority regulations, e.g. European Pharmacopeia.

All the problems above are due to the presence of humidity within thedry precursor compositions.

In prior art this has been solved by preparing granulates of thedifferent components and creating different layers of the differentcomponents within each granulate, like disclosed in EP0567452 orEP1714657.

However, this still may give rise to interactions between the differentlayers, and it is also a time-consuming matter of providing a completelyand properly dissolved granulate for the preparation of theready-for-use dialysis solution. Further, it is difficult to ensureproper composition and concentration of the different components bothwithin the granulate and thus also within the finally preparedready-for-use dialysis solution.

SUMMARY OF THE INVENTION

One object of the present invention is to provide a dialysis precursorcomposition which show further improved stability, limited chemicaldegradation and increased shelf life.

Another object of the present invention is to provide a dialysisprecursor composition which give rise to further cost savings andfurther improved environmental benefits.

These objects are achieved, in full or at least in part, by a dialysisacid precursor composition according to claim 1, with differentembodiments defined by dependent claims 2-6.

These objects are also achieved, in full or at least in part, by amethod according to claim 7, and a use of the dialysis acid precursorcomposition according to claims 8 and 9.

The present invention concerns a dialysis acid precursor composition foruse during preparation of a dialysis acid concentrate solution and forfurther mixing with water and a bicarbonate containing concentrate intoa ready-for-use dialysis solution. Said dialysis acid precursorcomposition consists of powder components comprising sodium chloride, atleast one dry acid and at least one calcium salt, and optionallypotassium salt, magnesium salt, and glucose. According to the inventionsaid at least one calcium salt and said optional glucose, i.e. ifglucose is present, are present as anhydrous components in said dialysisacid precursor composition. Further, said dialysis acid precursorcomposition is sealed in a moisture-resistant container with a watervapour transmission rate less than 0.3 g/m²/d at 38° C./90% RH.

The present invention further concerns a method of providing a dialysisacid concentrate solution for dilution with water and a bicarbonatecontaining concentrate to produce a ready-for-use dialysis solution.According to the invention this method comprises:

(a) providing a dialysis precursor composition comprising sodiumchloride, at least one dry acid, and at least one calcium salt,optionally potassium salt, magnesium salt, and glucose, wherein said atleast one calcium salt and said optional glucose, i.e. if glucose ispresent, are present as anhydrous components in said dialysis acidprecursor composition,

(b) providing said dialysis precursor composition in a sealed,moisture-resistant container with a water vapour transmission rate lessthan 0.3 g/m²/d at 38° C./90% RH, and

(c) adding a prescribed volume of water to said dialysis precursorcomposition in said container and mixing thereof, thereby providing saiddialysis acid concentrate as a solution.

The present invention further concerns use of said dialysis acidprecursor composition for preparing a dialysis acid concentratesolution.

Finally, the present invention concerns use of said dialysis acidprecursor composition for preparing a dialysis solution, an infusionsolution, a replacement solution, a rinsing solution or a primingsolution.

Other embodiments of the present invention are evident from thedescription below and the dependent claims.

DETAILED DESCRIPTION OF THE INVENTION

A wide variety of different combinations and partitions of dry powdercomponents of normal dialysis solutions like potassium chloride,magnesium chloride, calcium chloride, glucose, sodium chloride, sodiumbicarbonate, dry acids like citric acid, glucono-δ-lactone, etc. wereprepared and put in a forced stability study. Matters like caking, lumpformation, discoloration and dissolution rate were investigated after 1month, 4 months and 10 months storage time.

It was identified that, as expected, sodium bicarbonate needs to beseparated from the other components due to carbon dioxide formation,calcium carbonate precipitation, and magnesium carbonate precipitation.However, when combining the remaining components of a normal dialysissolution the crystalline water attached to calcium chloride causedproblems with caking and lump formation within the powder compositionsand discoloration of glucose (if present). By replacing calcium chloridedihydrate with anhydrous calcium chloride, or another calcium salt notcontaining any crystalline water, the powder composition remainedstable, free flowing and no discoloration evolved. Thus, in order tomake sure that a stable composition is provided the container materialused for storing the composition should be moisture-resistant and notallow passage of an amount equal to or above the amount which equals thecrystalline water normally attached with the calcium salt. This isachieved with a container material having a water vapour transmissionrate less than 0.3 g/m²/d at 38° C./90% RH.

In another embodiment said container material has a water vapourtransmission rate less than 0.2 g/m²/d at 38° C./90% RH.

In another embodiment said container material has a water vapourtransmission rate between 0.05-0.3 g/m²/d at 38° C./90% RH.

In even another embodiment said container material has a water vapourtransmission rate between 0.05-0.2 g/m²/d at 38° C./90% RH.

In another embodiment said container material has a water vapourtransmission rate between 0.1-0.3 g/m²/d at 38° C./90% RH.

In even another embodiment said container material has a water vapourtransmission rate between 0.1-0.2 g/m²/d at 38° C./90% RH.

According to the invention said dialysis acid precursor compositionconsists of powder components comprising sodium chloride, at least onedry acid and at least one calcium salt, and optionally potassium salt,magnesium salt, and glucose, wherein said at least one calcium salt andsaid optional glucose are present as anhydrous components in saiddialysis acid precursor composition within the moisture-resistantcontainer.

In other embodiments of the present invention said at least one dry acidis selected from the group comprising lactic acid, citric acid, gluconicacid, glucono-δ-lactone, N-acetyl cystein and α-lipoic acid. Thus, acombination of dry acids may be used within said dialysis acid precursorcomposition, and by providing a combination of different dry acids,other functions and effects, in addition to said acidic function, may beprovided, like for instance antioxidative effects (as with citric acid,gluconic acid, glucono-δ-lactone, N-acetyl cystein and α-lipoic acid),anticoagulation effects (as with citric acid) and so forth.

In even further embodiments said at least one calcium salt in saiddialysis acid precursor composition, is selected from the groupcomprising anhydrous calcium chloride, calcium gluconate, calciumcitrate (tricalcium dicitrate), calcium lactate and calciumα-ketoglutarate. Also here a combination of different calcium salts maybe used in order to tailor specific add-on features, like antioxidativeeffects from calcium gluconate, or anticoagulation effects from calciumcitrate, and so forth.

In one embodiment said at least one calcium salt in said dialysis acidprecursor composition comprises anhydrous calcium chloride. By usinganhydrous calcium chloride in a dry dialysis acid precursor composition,the anhydrous component will act as desiccant if any water wouldtransport into the bag.

In one embodiment said at least one calcium salt in said dialysis acidprecursor composition is selected from the group comprising calciumgluconate, calcium citrate and calcium lactate.

In other embodiments, in which magnesium salt is present, said magnesiumsalt in said dialysis acid precursor composition, is at least one chosenfrom the group comprising magnesium chloride with different degree ofhydration, e.g. magnesium chloride hexahydrate or magnesium chloridedihydrate. In one embodiment said dialysis precursor composition isprovided in a specific amount and is configured to be mixed with aprescribed volume of water within said moisture-resistant container toprovide a dialysis acid concentrate solution. Thus, saidmoisture-resistant container is configured to receive and dispensesolutions up to said prescribed volume.

In one embodiment said prescribed volume may be within the range of from1 to 8 L.

In another embodiment said prescribed volume may be within the range offrom 5-20 L.

In even another embodiment said prescribed volume may be within therange of 300-1000 L.

Further, in one embodiment said dialysis acid concentrate solution isconfigured and provided to be diluted within the range of 1:30 to 1:50with water and a bicarbonate concentrate.

The present invention further concerns a method of providing a dialysisacid concentrate solution. Said dialysis acid concentrate solution isfurther intended to be mixed with additional water and a bicarbonateconcentrate to produce a ready-for-use dialysis solution. According tothe invention said method comprises (a) providing a dialysis precursorcomposition comprising sodium chloride, at least one dry acid, and atleast one calcium salt, optionally potassium salt, magnesium salt, andglucose, wherein said at least one calcium salt and said optionalglucose are present as anhydrous components in said dialysis acidprecursor composition, (b) providing said dialysis precursor compositionin a sealed, moisture-resistant container with a water vapourtransmission rate less than 0.3 g/m²/d at 38° C./90% RH, and (c) addinga prescribed volume of water to said dialysis precursor composition insaid container and mixing thereof, thereby providing said dialysis acidconcentrate as a solution.

Sodium chloride is provided in such a quantity in saidmoisture-resistant container that a concentration within the range of2.55-5.5 M sodium chloride is provided in the dialysis acid concentratesolution when a prescribed volume of water has entered into saidmoisture-resistant container.

Said dry acid is provided in such a quantity in said moisture-resistantcontainer that a concentration within the range of 60-200 mEq/L H⁺(acid) is provided in the dialysis acid concentrate solution when aprescribed volume of water has entered into said moisture-resistantcontainer.

Further, said at least one calcium salt is provided in such a quantityin said moisture-resistant container that a concentration within therange of 30-125 mM calcium ions is provided in the dialysis acidconcentrate solution when a prescribed volume of water has entered intosaid moisture-resistant container.

If present, said magnesium salt is provided in such a quantity in saidmoisture-resistant container that a concentration within the range of7.5-50 mM magnesium ions is provided in the dialysis acid concentratesolution when a prescribed volume of water has entered into saidmoisture-resistant container.

If present, potassium salt is provided in such a quantity in saidmoisture-resistant container that a concentration within the range of0-200 mM potassium ions is provided in the dialysis acid concentratesolution when a prescribed volume of water has entered into saidmoisture-resistant container.

If present, glucose is provided in such a quantity in saidmoisture-resistant container that a concentration within the range of0-100 g/L is provided in the dialysis acid concentrate solution when aprescribed volume of water has entered into said moisture-resistantcontainer.

In one embodiment said dry dialysis acid precursor composition comprisesthe different components in such an amount that, when said dry dialysisacid precursor composition has been dissolved and mixed with water andbicarbonate, it provides a ready-for-use dialysis solution comprisingfrom about 130-150 mM of sodium ions, from about 0 to 4 mM of potassiumions, from about 1-2.5 mM of calcium ions, from about 0.25 to 1 mM ofmagnesium ions, from about 0 to 2% (g/l) glucose from about 85 to 134 mMchloride ions, from about 2 to 4 mEq/L acid, and from about 20 to 40mEq/L bicarbonate ions.

Thus, the present invention provides a prepackaged container with a drydialysis acid precursor composition for use during preparation of adialysis acid concentrate solution and for mixing with water and abicarbonate containing concentrate into a ready-for-use dialysissolution, wherein said dialysis acid precursor composition consists ofpowder components comprising sodium chloride, at least one dry acid andat least one calcium salt. Optionally said dialysis acid precursorcomposition further comprises potassium salts, magnesium salts, andglucose. According to the invention said at least one calcium salt ispresent as anhydrous component in said dialysis acid precursorcomposition and said dialysis acid precursor composition is sealed in amoisture-proof container with a water vapour transmission rate less than0.3 g/m²/d at 38° C./90% RH.

EXAMPLES

By way of example, and not limitation, the following examples identify avariety of dialysis acid precursor compositions pursuant to embodimentsof the present invention.

In examples 1-4, the tables show the content of dialysis acid precursorcompositions for dilution 1:35. The prescribed volume of each dialysisacid concentrate solution (DACS in tables below) is 5.714 L, and thefinal volume of each ready-for-use dialysis solution (RFUDS in tablesbelow) is 200 L.

Example 1

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1169 3500 100 Potassium chloride 29.81 70 2 Magnesium chloride20.33 17.5 0.5 hexahydrate Calcium gluconate 129.1 52.5 1.5 Citric acid38.42 35 1 Glucose anhydrous 200 194.4 5.55

Example 2

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1169 3500 100 Magnesium chloride 20.33 17.5 0.5 hexahydrateCalcium gluconate 129.1 52.5 1.5 Citric acid 38.42 35 1 Glucoseanhydrous 400 388.8 11.11

Example 3

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1169 3500 100 Potassium chloride 29.81 70 2 Magnesium chloride20.33 17.5 0.5 hexahydrate Calcium chloride 33.30 52.5 1.5 anhydrousGlucono-delta-lactone 142.5 140 4 Glucose anhydrous 200 194.4 5.55

Example 4

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1169 3500 100 Potassium chloride 29.81 70 2 Magnesium chloride20.33 17.5 0.5 hexahydrate Calcium chloride 33.30 52.5 1.5 anhydrousCitric acid 38.42 35 1 Glucose anhydrous 200 194.4 5.55

In examples 5-7, the tables show the content of a dry acid precursorcomposition for dilution 1:45. The prescribed volume of each dialysisacid concentrate solution (DACS in tables below) is 5.33 L, and thefinal volume of each ready-for-use dialysis solution (RFUDS in tablesbelow) is 240 L.

Example 5

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1402 4500 100 Potassium chloride 53.68 135 3 Magnesium chloride24.40 22.5 0.5 hexahydrate Calcium gluconate 129.1 56.25 1.25 Citricacid 46.10 45 1

Example 6

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1402 4500 100 Magnesium chloride 24.40 22.5 0.5 hexahydrateCalcium gluconate 180.8 78.75 1.75 Citric acid 46.10 45 1 Glucoseanhydrous 240 250 5.55

Example 7

Amount Conc in Conc in Ingredient (g) DACS (mM) RFUDS (mM) Sodiumchloride 1402 4500 100 Potassium chloride 71.57 180 4 Magnesium chloride24.40 22.5 0.5 hexahydrate Calcium chloride 26.64 45 1 anhydrous Citricacid 46.10 45 1 Glucose anhydrous 240 250 5.55

While the invention has been described in connection with what ispresently considered to be the most practical embodiments, it is to beunderstood that the invention is not to be limited to the disclosedembodiments, but on the contrary, is intended to cover variousmodifications and equivalents included within the spirit and the scopeof the appended claims.

The invention claimed is:
 1. A dialysis acid precursor composition foruse during preparation of a dialysis acid concentrate solution and formixing with water and a bicarbonate containing concentrate into aready-for-use dialysis solution, the dialysis acid precursor compositionconsisting of: powder components comprising a sodium chloride powder, atleast one dry acid powder and at least one calcium chloride powder,wherein the calcium chloride is present as an anhydrous component in thedialysis acid precursor composition, and the calcium chloride is in aquantity such that a concentration of 30-125 mM calcium ions is providedin the dialysis acid concentrate solution.
 2. A dialysis precursorcomposition according to claim 1, wherein said at least one dry acid isselected from the group comprising lactic acid, citric acid, gluconicacid, glucono-δ-lactone, N-acetyl cystein and α-lipoic acid.
 3. Adialysis precursor composition according to claim 1, wherein saiddialysis precursor composition is configured to be mixed with aprescribed volume of water to provide a dialysis acid concentratesolution.
 4. The dialysis precursor composition of claim 1 wherein thepowder components further comprise at least one of a potassium salt, amagnesium salt and an anhydrous glucose.